Pulmonary Hypertension in Intensive Care Units: An Updated Review.

Pulmonary hypertension (PH) is a condition associated with high morbidity and mortality. Patients with PH who require critical care usually have severe right ventricular (RV) dysfunction. Although different groups of PH have different etiologies, pulmonary vascular dysfunction is common in these groups. PH can lead to increased pulmonary artery pressure, which can ultimately cause RV failure. Clinicians should be familiar with the presentations of this disease and diagnostic tools. The contributing factors, if present (e.g., sepsis), and coexisting conditions (e.g., arrhythmias) should be identified and addressed accordingly. The preload should be optimized by fluid administration, diuretics, and dialysis, if necessary. On the other hand, the RV afterload should be reduced to improve the RV function with pulmonary vasodilators, such as prostacyclins, inhaled nitric oxide, and phosphodiesterase type 5 inhibitors, especially in group 1 PH. Inotropes are also used to improve RV contractility, and if inadequate, use of ventricular assist devices and extracorporeal life support should be considered in suitable candidates. Moreover, vasopressors should be used to maintain systemic blood pressure, albeit cautiously, as they increase the RV afterload. Measures should be also taken to ensure adequate oxygenation. However, mechanical ventilation is avoided in RV failure. In this study, we reviewed the pathophysiology, manifestations, diagnosis, monitoring, and management strategies of PH, especially in intensive care units.

Patients with PH are admitted to the intensive care unit (ICU) for a variety of reasons (Table 2). ICU admission due to undiagnosed group 1 PH or pulmonary arterial hypertension (PAH) has decreased substantially as a result of improved knowledge about the disease (3). The majority of these patients are treated with PAH-specific drugs before ICU admission (4, 5). There are seven approved  Prostacyclin is a potent vasodilator, which acts by increasing the level of cyclic adenosine monophosphate. A decrease in the production of prostacyclin has been reported in patients with PAH. Prostacyclin also reduces vascular remodeling, inflammation, platelet aggregation, and thrombosis. Thromboxane, a potent vasoconstrictor, increases due to PAH, and an imbalance in prostacyclin/thromboxane production is a proposed mechanism in the development of PAH (19)(20)(21)(22)(23)(24). NO, which is produced by endothelial cells, acts by increasing cyclic guanosine monophosphate (cGMP) to cause vasodilation.
Decreased production of NP due to endothelial dysfunction has been shown to play a role in PH (25-27).
Treatment of PH, especially PAH as the most studied variant of PH, focuses on different targets of these three major pathways. Currently, there are nine drugs in four classes, approved for the treatment of PAH. These classes include prostanoids, soluble guanylate cyclase stimulators, endothelin receptor antagonists (ERAs), and phosphodiesterase type 5 (PDE5) inhibitors (6, 28).
Normal pulmonary circulation is a so-called "highflow, low-pressure" system. Its maintenance requires the reduction of pulmonary vascular resistance (PVR) in response to increased blood flow. Disruption in the normal vasodilatory reserve of pulmonary vessels and pulmonary vascular dysfunction are known to interrupt this system.
The relationship between pressure, flow, and resistance is understandable based on the following equation: where PVR represents the pulmonary vascular resistance, mPAP is the mean pulmonary artery pressure, PCWP is the pulmonary capillary wedge pressure, and CO is the cardiac output. Due to the great potential of pulmonary vessels in vasodilation (ability of PVR to decrease significantly), an increased flow (measured as CO in the equation) does not lead to a considerable increase in PAP in physiological conditions. However, when this potential is compromised, the increased flow causes PAP to rise.
As described earlier, there are multiple etiologies for PH, but RV dysfunction and ultimately RV failure are common in severely ill patients. It is well established that RV function is an important predictor of survival in patients with PH (7, 9). As a result, RV failure should be emphasized in the treatment of patients with PH in ICUs.
Most studies on ventricular failure are restricted to the LV.
However, some findings can be also true for the right ventricle (RV). The RV, compared to the LV, has a thinner wall and a more complex geometry. From the front view, it is somewhat triangular (compared to the conical LV), and from the cross-sectional view, it is crescent-shaped. It has a convex free wall and a concave interventricular septum (29-31). Based on the Laplace's law (see below), wall stress in a spherical or cylindrical chamber is directly According to the Frank-Starling law, SV of a ventricle is dependent on three factors: 1) preload, 2) afterload, and 3) inotropy (contractility). With a constant afterload and inotropy, SV is determined by preload.
Dilation leads to increased sarcomere length in physiological limits, resulting in increased contractile force.
In a chronically volume-overloaded RV, SV is relatively preserved with hypertrophy of RV. However, with further volume overload or acute volume/pressure overload of the RV (e.g., acute pulmonary embolism), RV fails to maintain a normal SV. This is primarily due to the increased length of sarcomeres beyond their physiological limit, which results in decreased contractility (36). In this section, management strategies will be discussed in three main categories: optimization of 1) RV preload, 2) RV afterload, and 3) RV contractility (36, 105). Instead of a step-wise approach, all three categories must be considered simultaneously as they are intricately related.

Right ventricle preload
Assessment of the patient's volume status is a very important and challenging issue, especially in critical care. and deterioration of RV and LV function ( Figure 1).

Other measures
Graded balloon dilation atrial septostomy may be